Defining the factors that affect solute permeation of gap junction channels

Abstract

This review focuses on the biophysical properties and structure of the pore and vestibule of homotypic gap junction channels as they relate to channel permeability and selectivity. Gap junction channels are unique in their sole role to connect the cytoplasm of two adjacent cells. In general, these channels are considered to be poorly selective, possess open probabilities approximating unity, and exhibit mean open times ranging from milliseconds to seconds. These properties suggest that such channels can function as delivery pathways from cell to cell for solutes that are significantly larger than monovalent ions. We have taken quantitative data from published works concerning unitary conductance, ion flux, and permeability for homotypic connexin 43 (Cx43), Cx40, Cx26, Cx50, and Cx37, and performed a comparative analysis of conductance and/or ion/solute flux versus diffusion coefficient. The analysis of monovalent cation flux portrays the pore as equivalent to an aqueous space where hydrogen bonding and weak interactions with binding sites dominate. For larger solutes, size, shape and charge are also significant components in determining the permeation rate. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

Keywords: Conductance; Connexin; Gap junction; Permeability; Selectivity.

Fig. 1

Comparison of connexin permeability to monovalent ions. (A) Plots showing normalized unitary conductances with various monovalent solutes, all relative to Cs, for Cx43 (Cs, Rb, K, Na, LI, TMA, TEA), Cx40 (Cs, Rb, K, Na, Li, TMA, TEA), Cx37 (Cs, Rb, K, Na, Li, TMA, TEA), Cx26 (Cs, K, Na, TEA), and Cx50 (Cs, K, Na) versus the solutes’ respective diffusion coefficients. The solid lines represent the data fit to a linear regression with the following R² values: 0.92 (Cx43), 0.99 (Cx40), 0.85 (Cx37), 0.88 (Cx26), and 0.93 (Cx50). (B) Plots of normalized equivalent solute conductivity (○) versus the respective diffusion coefficient along with normalized Cx43 conductance (●) for Cs, Rb, K, Na, Li, TMA, and TEA, all relative to Cs. See text for references on derivation of data and details.

Fig. 2

Summary of connexin permeability to ions, dyes, metabolites, morpholinos, and siRNA. Flux data of different solutes normalized to K⁺ flux plotted versus their respective diffusion coefficients for Cx43 (Cs, Rb, K, Na, Li, TMA, TEA, cAMP, LY, 12mer, 16mer, 24mer, 21 siRNA), Cx40 (Cs, Rb, K, Na, Li, TMA, TEA, cAMP, LY), and Cx26 (Cs, K, Na, cAMP, LY). The data has been plotted on a log scale to better depict lowered flux for larger solutes like morpholinos and siRNA. See text for references on derivation of data and details.

Fig. 3

(A) Linear plot of different solutes flux data normalized to K⁺ versus respective diffusion coefficients for Cx43. The solid line represents monovalent data fit to a linear regression (R² = 0.978) and the dashed lines are the 95% confidence intervals. The flux data for the large solutes: 12mer, 16mer, 24mer, 21 siRNA were not fit to linear regression. (B) Normalized flux data for large solutes 12mer, 16mer, 24mer, 21 siRNA plotted on expanded scale versus cube root of their respective molecular weight (see text for details).

Fig. 4

Schematic of a gap junction pore depicting the factors that affect solute transfer via gap junction channels.